Citations

Abstract Background Injecting soft tissue fillers into the deep plane of the forehead carries the risk of injection-related visual compromise due to the specific course of the arterial vasculature. Objectives The aim of this study was to investigate the 2- and 3-dimensional location of the change of plane of the deep branch of the supratrochlear and supraorbital artery, respectively. Methods A total of 50 patients (11 males and 39 females; mean age, 49.76 [13.8] years, mean body mass index, 22.53 [2.6] kg/m2) were investigated with ultrasound imaging. The total thickness and the distance of the arteries from the skin and bone surface were measured with an 18-MHz broadband compact linear array transducer. Results The deep branch of the supraorbital artery changed plane from deep to superficial to the frontalis muscle at a mean distance of 13 mm (range, 7.0-19.0 mm) in males and at 14 mm (range, 4.0-24.0 mm) in females and for the deep branch of the supratrochlear artery at a mean distance of 14 mm in males and females (range, 10.0-19.0 in males, 4.0-27.0 in females) when measured from the superior orbital rim. Conclusions Based on the ultrasound findings in this study, it seems that the supraperiosteal plane of the upper and lower forehead could be targeted during soft tissue filler injections because the deep branches of both the supraorbital and supratrochlear arteries do not travel within this plane. The superficial plane of the lower forehead, however, should be avoided due to the unpredictability and inconsistent presence of the central and paracentral arteries. Level of Evidence: 4

159 Background: Tumour tissue from metastatic castration-resistant prostate cancer (mCRPC) harbors frequent copy number variations (CNVs) in the phosphatidylinositol-3-kinase (PI3K)/Akt-signaling pathway. However, identifying CNVs in plasma cell-free DNA (cfDNA) has proven challenging. With emerging data supporting Akt inhibition in PTEN-deficient mCRPC, cfDNA assays for robustly identifying PI3K/Akt pathway aberrations including CNVs are urgently required. Methods: In this multi-institutional prospective biomarker study, we used the Predicine cfDNA assay, optimised for CNV detection, to perform targeted sequencing in 231 mCRPC patients in two independent cohorts (Australian, n = 78; US, n = 153). Kaplan-Meier survival estimates and multivariable Cox regression analysis were used to assess associations between genomic aberrations and progression-free survival (PFS) and overall survival (OS). Results: PTEN loss and PIK3CA gain were detected in 37% (85/231) and 17% (39/231) of patients, respectively. Poorer outcomes were observed in patients with PI3K/Akt pathway aberrations, including those with dual PTEN loss and PIK3CA gain (HR 2.3, 95% CI 1.2-4.4). Similarly, cumulative CNV burden in the PI3K/Akt and AR pathways (0 vs 1 vs ≥2 CNVs in Australian cohort: median OS 33.5 vs 17.2 vs 9.7 months, p< 0.001; 0 vs 1 vs ≥2 CNVs in US cohort: median OS 35.5 vs 14.3 vs 9.2 months, p< 0.001) was associated with significantly worse clinical outcomes. Notably, 21% (31/146) of PTEN-neutral patients harbored other alterations in the PI3K/Akt pathway. Conclusions: Our cfDNA assay readily detected PI3K/Akt pathway CNVs, with the prevalence of PTEN loss comparable to prior tissue sequencing studies. CNVs in the PI3K/Akt pathway were associated with deleterious clinical outcomes, especially when concurrent with AR gain. Additional PI3K/Akt pathway aberrations were found in approximately one-fifth of PTEN-neutral mCRPC. Collectively, our data demonstrate the potential utility of profiling cfDNA to facilitate and optimize patient selection for treatment with Akt inhibitors in mCRPC. [Table: see text]

Abstract Background The most severe complications following soft tissue filler injections result from the intraarterial administration of the filler product. Although hyaluronic acid–based filler can be trans-arterially dissolved with hyaluronidase, no information is available on calcium hydroxylapatite (CaHA)-based fillers. Objective The authors sought to test whether CaHA-based fillers can be trans-arterially dissolved by sodium thiosulfate (STS) when evaluated in cadaveric and in vitro models. Methods Human cadaveric facial arterial segments were each filled with 0.2 cc of commercially available CaHA product and submerged for 24 hours in 4 different STS-containing solutions: 10 cc STS (300 mg/cc) (pure, 1:1 dilution, 1:2 dilution), 0.9% saline and 10 cc STS (300 mg/cc), and 300 IU (bovine) hyaluronidase in a 1:1 ratio. Results Intraarterial CaHA was detected in human facial artery segments after 24 hours independent of the STS concentration employed. Submerging the arterial segments in STS (300 mg/cc) and 300 IU (bovine) hyaluronidase (1:1 ratio) also did not dissolve the intraarterial CaHA product. Gray scale analyses did show, however, that increasing concentrations of STS resulted in increased disintegration of CaHA in an in vitro experimental setting. Conclusions The results of this study indicate that STS is limited in its potential to dissolve intraarterial CaHA of cadaveric human facial arteries, despite the fact that it appears effective when in direct contact with the CaHA. Adverse events caused by intraarterial administration of CaHA-based fillers still lack a suitable antidote.

Background Activating mutations in JAK2 are the molecular hallmark of PV. However, achieving molecular remission is not a validated endpoint in PV, as its correlation with patient-relevant endpoints, such as thrombotic events or disease progression, is not well established. The expression of MDM2, a negative regulator of wild-type p53, is significantly higher in CD34+ cells from patients with PV vs those from healthy controls. Therefore, MDM2 antagonists such as idasanutlin (idasa) may have selective and potentially disease-modifying effects in PV. This exploratory analysis reports baseline mutational profiling and serial measurements of JAK2 V617F variant allele frequency (VAF) from patients treated with idasa in the Phase II NP39761 study (NCT03287245). Methods Patients with PV, as defined by the 2016 World Health Organization criteria, were eligible for inclusion if their disease was HU resistant/intolerant according to European LeukemiaNet criteria and they were phlebotomy dependent (≥ 1 phlebotomy in the 16-wk period prior to screening). Prior PV therapy with ruxolitinib and/or interferon was allowed. Idasa was given orally once daily on days 1-5 of 28-day cycles for up to 24 mo. The starting dose was 150 mg, but dose increase (to 200 mg) or decrease (to 100 mg) was allowed per protocol-defined criteria. The primary efficacy endpoints were hematocrit control (HTC), defined as maintaining acceptable hematocrit levels with ≤ 1 phlebotomy between cycle 1, day 1 (C1D1) and wk 8 and no phlebotomy after wk 8, and complete hematologic remission (CHR), defined as HTC together with platelets &lt; 400 × 109/L and white blood cell count &lt; 109/L on the day of response assessment (or most recent test). JAK2 V617F VAF was analyzed at screening and at C3D28, C5D28 and wk 32. The JAK2 V617F VAF was determined using quantitative polymerase chain reaction. Baseline blood samples were sequenced using the Foundation Medicine FoundationOne Heme next-generation sequencing panel, which interrogates &gt; 400 DNA-sequenced genes, to explore the genetic landscape of PV beyond JAK2 V617F. Results All 27 patients enrolled in the study harbored JAK2 V617F. Baseline and ≥ 1 later JAK2 VAF measurements were available in 23 patients, allowing for analysis. The median age was 56 y (range, 34-74), and 7 patients (26%) had been previously treated with ruxolitinib. Median treatment duration was 257 days (range, 5-677), and the median number of treatment cycles was 8 (range, 1-22). JAK2 V617F VAFs at baseline were highly variable, ranging from 7% to 96% (median, 66%). A reduction in JAK2 V617F VAF was observed as early as after 3 cycles (median reduction, 39%; n = 19) and was sustained in patients receiving treatment, with a median reduction of 58% at C5D28 (n = 17) and of 76% at wk 32 (n = 13). The median reductions in JAK2 V617F VAF were significantly higher for patients with CHR and HTC than in nonresponders on C3D28 (CHR, P &lt; 0.01; HTC, P = 0.04) and C5D28 (CHR, P &lt; 0.01; HTC, P = 0.03), with a similar trend also at wk 32 (CHR, P = 0.06; HTC, P = 0.19) (Figures). Baseline targeted sequencing (n = 16) identified several additional subclonal mutations. However, no TP53 mutations were detected. Variants in TET2 and ASXL1 were detected in 37% (6 of 16) and 20% (3 of 16) of patients, with VAFs of 2%-51% and 38%-50%, respectively. Notably, 68% of the patients had variants detected in 1 to 3 DNA repair genes, including ATM (VAF, 47%-52%), ATR (VAF, 49%), BRCA2 (VAF, 47%-51%), PARP1 (VAF, 52%), PARP3 (VAF, 48%), FANCM (VAF, 47%-50%), BLM (VAF, 48%) and MSH3 (VAF, 49%). In the absence of sequencing of patient-matched non-hematologic tissue and the VAFs being ≈50%, it is possible some of these variants are germline. Whether such variants predispose to PV is unknown. Conclusions Idasa has relevant clinical activity in patients with PV who are resistant to or intolerant of HU and showed rapid JAK2 V617F VAF reduction in a subset of patients as early as after 3 treatment cycles. The median JAK2 VAF reduction was significantly greater in patients who achieved CHR and HTC after 3 and 5 cycles of idasa treatment, suggesting that early molecular response was associated with higher likelihood of clinical response. Baseline mutations were seen in several genes commonly mutated in PV. A high frequency of variants in DNA repair genes has not previously been reported in PV and may contribute to genomic instability in this disease. Figure Disclosures Passamonti: Roche: Other: Support of parent study and funding of editorial support; BMS: Speakers Bureau; Novartis: Speakers Bureau. El-Galaly:F. Hoffmann-La Roche: Current Employment, Other: Support of parent study and funding of editorial support. Gerds:Celgene: Consultancy, Research Funding; Gilead Sciences: Research Funding; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; AstraZeneca/MedImmune: Consultancy; Roche/Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; Pfizer: Research Funding; Apexx Oncology: Consultancy; Sierra Oncology: Research Funding. Gupta:Incyte: Honoraria, Research Funding; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy. Higgins:Roche: Current Employment, Current equity holder in publicly-traded company, Other: Support of parent study and funding of editorial support. Huw:Roche: Current Employment, Other: Support of parent study and funding of editorial support. Maffioli:Roche: Other: Support of parent study and funding of editorial support. Mesa:Sierra Oncology: Consultancy; Incyte: Research Funding; Samus Therapeutics: Research Funding; Promedior: Research Funding; Genentech: Research Funding; Novartis: Consultancy; CTI BioPharma: Research Funding; LaJolla Pharmaceutical Company: Consultancy; AbbVie: Research Funding; Bristol Myers Squibb: Research Funding. Rambaldi:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yacoub:Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support; Ardelyx: Current equity holder in publicly-traded company. Mascarenhas:Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution).

Background PV is a clonal myeloid neoplasm characterized by activating mutations in JAK2 and increased red blood cell production. Reduction of thrombosis risk through lowering of hematocrit (Hct) and thus blood viscosity is critical, but management of constitutional symptoms is also important. HU is an effective and well-tolerated first-line treatment (tx) for PV, but pts who develop resistance to or intolerance of HU have limited tx options. A Phase I study of idasanutlin, an MDM2 antagonist leading to increased p53 activity, showed encouraging efficacy and potential disease-modifying effects via rapid reduction in JAK2 V617F variant allele frequency in 11 pts with PV. These results prompted the larger, international Phase II study of idasanutlin in HU-resistant/intolerant PV (NCT03287245); data from the initial phase of the study are reported here. Methods Pts meeting the 2016 WHO criteria for PV were eligible for inclusion if they had HU-resistant/intolerant disease according to the European LeukemiaNet (ELN) criteria and were phlebotomy dependent (≥ 1 phlebotomy in the 16-wk period prior to screening). Prior PV tx with ruxolitinib (rux) or interferon was allowed. Idasanutlin was given orally once daily on days 1-5 of 28-day cycles for up to 24 mo. The starting dose was 150 mg; increase to 200 mg was allowed for non-responders at cycle 3, day 28, and reduction to 100 mg was permitted for toxicity and for pts treated beyond cycle 12. Antiemetic prophylaxis was mandatory in cycle 1 throughout the study and later became mandatory in all cycles. The primary endpoint (wk 32) was the composite response of Hct control (HTC) and spleen volume reduction &gt; 35% by CT/MRI in pts with splenomegaly (&gt; 450 cm3) and HTC alone in pts without splenomegaly. Key secondary endpoints included safety, complete hematologic response (CHR; defined as HTC and normalization of platelets/leukocytes) and ELN response. Results A total of 27 pts were included in this study and received tx with idasanutlin. Median age was 56 years (range, 34-74) and 16 pts (59.3%) were male (Table 1). All pts had JAK2 V617F mutation; 7 had previous exposure to rux. Median tx duration was 257 days (range, 5-677); the median number of treatment cycles was 8 (range, 1-23). Dose modifications occurred in 17 pts (63.0%; Table 2). A total of 3 serious AEs occurred: atrial flutter, atrial fibrillation and nausea/vomiting (n = 1 each). The serious cardiac AEs occurred in pts with pre-existing hypertension and a past incident of heart failure not symptomatic upon enrollment, respectively. No deaths, transformation to acute myeloid leukemia, progression to myelofibrosis or thrombotic events occurred during the study. AEs occurring in ≥ 15% of pts are listed in Table 3; gastrointestinal toxicity and fatigue were the most common events. The population for primary endpoint evaluation consisted of pts with response assessed at wk 32 (n = 16). One of 13 pts with baseline splenomegaly achieved a composite response (7.7%; Table 4). Nine of 16 pts (56.3%) among all evaluable pts achieved HTC: 6 of 11 rux-naive pts (54.5%) and 3 of 5 rux-exposed pts (60.0%). Eight of 13 pts (61.5%) among all pts had HTC duration ≥ 12 wk beyond wk 32: 5 of 9 rux-naive pts (55.6%) and 3 of 4 rux-exposed pts (75.0%). At wk 32, 8 of 16 pts (50.0%) achieved a CHR, with 6 of 13 (46.2%) having a CHR duration ≥ 12 wk beyond wk 32. Overall response rates per modified ELN response criteria in pts with baseline splenomegaly, pts without baseline splenomegaly and in all pts were 69.2% (9 of 13), 66.7% (2 of 3) and 68.8% (11 of 16), respectively; 9 of 15 pts (60%) among all pts had a response duration ≥ 12 wk beyond wk 32. Median (range) laboratory value changes at wk 32 were: platelets, −253 × 109/L (−2083 to +175) and leukocytes, −4.8 × 109/L (−25.3 to +3.4). At wk 32, 6 of 14 pts (42.9%) had a ≥ 50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score. Conclusions Idasanutlin showed relevant clinical activity in pts with HU-resistant/intolerant PV and also in a subset of pts with prior rux tx. However, the low-grade gastrointestinal toxicity profile of idasanutlin was not effectively mitigated with antiemetic prophylaxis and led to frequent discontinuations. These results iterate the importance of tolerability of novel therapies administered over the long term for pts with PV. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Higgins:Roche: Current Employment, Current equity holder in publicly-traded company, Other: Support of parent study and funding of editorial support. Anders:Roche: Current Employment, Other: Support of parent study and funding of editorial support. Burbury:Roche: Other: Support of parent study and funding of editorial support. El-Galaly:F. Hoffmann-La Roche: Current Employment, Other: Support of parent study and funding of editorial support. Gerds:Roche/Genentech: Research Funding; Apexx Oncology: Consultancy; AstraZeneca/MedImmune: Consultancy; Pfizer: Research Funding; Imago Biosciences: Research Funding; Gilead Sciences: Research Funding; Incyte Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding; CTI Biopharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Gupta:Pfizer: Consultancy; Incyte: Honoraria, Research Funding; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kovic:Roche: Other: Support of parent study and funding of editorial support. Maffioli:Roche: Other: Support of parent study and funding of editorial support. Mesa:AbbVie: Research Funding; Sierra Oncology: Consultancy; CTI BioPharma: Research Funding; LaJolla Pharmaceutical Company: Consultancy; Bristol Myers Squibb: Research Funding; Genentech: Research Funding; Samus Therapeutics: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Incyte: Research Funding. Rambaldi:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.. Vannucchi:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yacoub:Roche: Other: Support of parent study and funding of editorial support; Dynavax: Current equity holder in publicly-traded company; Novartis: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company.

Abstract Background: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. Methods: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). Results: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03–1.13; OR: 3.33, 95% CI, 2.46–4.50; and OR: 1.15, 95% CI, 1.02–1.29, respectively). Conclusions: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis. Impact: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.

348 Background: The proportion of females in medicine is increasing (approx. 50% in medical school/workforce), but disparities in female authorship in oncology research publications exist; female corresponding authorship reportedly ranges from 7.2-39.1% in oncology clinical trials (Ludmir et al 2019). This study aimed to describe and assess factors associated with female first and senior authorship in later phase systemic clinical trials in BTC and to identify any changes over time. Methods: Embase/Medline were used to identify final primary trial publications in BTC (2000-2020) (excluding phase I (PI) (expected to move to later phase), mixed tumour site trials, reviews, editorials and trial-in-progress publications). Gender was determined by inspection of names, google search and author communication. Chi-square tests and log regression were used to assess factors associated with female first and senior authorship, including changes over time (STATA16). Results: Of 501 publications, 163 met inclusion criteria; 80% single-arm PII and 15% and 5% randomised PII and PIII respectively; 73% enrolled ≤50 patients. Tumour primary sites were all BTC: 86%, cholangiocarcinoma: 8%, gallbladder cancer: 6%; 80% involved chemotherapy, 13% targeted therapy and 5% localised/systemic combinations; 65% were in first-line (1L) advanced setting, 17% post 1L, 13% advanced non-specified and 5% neo-adjuvant/adjuvant. Forty-eight percent received industry funding and 65% met primary end-point. Sixty-four percent were published post ABC-02 (Valle et al 2010). Publication impact factor (IF) was ≤5 in 50% and >20 in 12%. Median number of authors in all publications was 11. Geographic location of all first and senior authors were Asia (42%/42%), Europe (29%/29%), USA (24%/22%) and other (4%/6%), respectively. Median individual trial female author representation was 25%; there were no female authors in 12% of trials. Overall, female first and senior author representation was 21% and 11%, respectively. Median position of first female author was second. In publications with IF ≤20 and >20, there were 22% and 16% female first and 13% and 0% female senior authors, respectively. The phase of trial, journal IF, industry funding, or whether met primary end-point did not impact female first or senior author representation (all P>.05). There were more female senior authors associated with “other” geographic locations (40% in 10 trials) (P=.016) vs Asia (7%), Europe (8%) and USA (14%). There were no significant changes in female first or senior author representation over time (‘00-05: 21%/18%, ‘06-10: 27%/5%, ‘11-15: 15%/15%, ‘16-20: 22%/9%, P=.738, and P=.508 respectively). Conclusions: Female first and senior author representation in later phase systemic clinical trial publications in BTC is low and has not changed significantly over time. The underlying reasons for this imbalance need to be better understood and addressed.

266 Background: CCA is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in ~20% of intrahepatic CCAs, resulting in production of the oncometabolite D-2-hydroxyglutarate, which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of mutant IDH1 (m IDH1). ClarIDHy aimed to demonstrate the efficacy of IVO vs PBO in pts with unresectable or metastatic m IDH1 CCA. The primary endpoint was met with significant improvement in progression-free survival (PFS) by independent radiology center (IRC) with IVO vs PBO (hazard ratio [HR] = 0.37, p < 0.0001). Objective response rate (ORR) and stable disease for IVO were 2.4% (3 partial responses) and 50.8% (n = 63) vs 0% and 27.9% (n = 17) for PBO. IVO pts experienced significantly less decline in physical and emotional functioning domains of quality of life at cycle 2 day 1 vs PBO pts (nominal p < 0.05). Methods: Pts with m IDH1 CCA were randomized 2:1 to IVO (500 mg PO QD) or matched PBO and stratified by prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic m IDH1 CCA based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic progression. Primary endpoint: PFS by IRC. Secondary endpoints included overall survival (OS; by intent-to-treat), ORR, PFS (by investigator), safety, and quality of life. The planned crossover-adjusted OS was derived using the rank-preserving structural failure time (RPSFT) model. Results: As of 31 May 2020, ~780 pts were prescreened for an IDH1 mutation and 187 were randomized to IVO (n = 126) or PBO (n = 61); 13 remain on IVO. Median age 62 y; M/F 68/119; 91% intrahepatic CCA; 93% metastatic disease; 47% had 2 prior therapies. 70% of PBO pts crossed over to IVO. OS data were mature, with 79% OS events in IVO arm and 82% in PBO. Median OS (mOS) was 10.3 months for IVO and 7.5 months for PBO (HR = 0.79; 95% CI 0.56–1.12; one-sided p = 0.093). The RPSFT-adjusted mOS was 5.1 months for PBO (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). Common all-grade treatment emergent adverse events (TEAEs, ≥ 15%) in the IVO arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade ≥ 3 TEAEs were reported in 50% of IVO pts vs 37% of PBO pts, with grade ≥ 3 treatment-related AEs in 7% of IVO pts vs 0% in PBO. 7% of IVO pts experienced an AE leading to treatment discontinuation vs 9% of PBO pts. There were no treatment-related deaths. Conclusions: IVO was well tolerated and resulted in a favorable OS trend vs PBO despite a high rate of crossover. These data – coupled with statistical improvement in PFS, supportive quality of life data, and favorable safety profile – demonstrate the clinical benefit of IVO in advanced m IDH1 CCA. Clinical trial information: NCT02989857.

Abstract High-specificity colorectal cancer screening is desirable to triage patients &lt;50 years for colonoscopy; however, most endorsed colorectal cancer screening tests have not been rigorously evaluated in younger populations. This prospective cross-sectional study determined the specificity of the multitarget stool DNA (mt-sDNA) test in an average-risk screening population of 45 to 49 year-olds. Specificity was the primary outcome and was measured in participants without colorectal cancer or advanced precancerous lesions [APL– advanced adenomas (AA), and sessile serrated lesions ≥10 mm], and in the subgroup of participants with negative colonoscopic findings. APL sensitivity was a secondary outcome. The evaluable cohort included those who completed the study without protocol deviations and had a usable mt-sDNA test. Of 983 enrolled participants, 816 formed the evaluable cohort, with a mean age of 47.8 (SD, 1.5) years; 47.7% were women. No participants had colorectal cancer, 49 had APL, 253 had nonadvanced adenomas (NAA), and 514 had negative colonoscopic findings. mt-sDNA test specificity was 95.2% (95% CI, 93.4–96.6) in participants with NAA or negative findings [96.3% (confidence interval (CI), 94.3%–97.8%)] in those with negative findings, and did not differ by sex (P = 0.75) or race (P = 0.36) in participants with NAA or negative findings. Sensitivity for APL was 32.7% (CI, 19.9–47.5%), with most APL (83.7%) measuring 10–19 mm and none having high-grade dysplasia. The area under the ROC curve for discriminating between APL and lesser findings was 0.72 (CI, 0.64–0.81). mt-sDNA's high specificity would help minimize risk from unnecessary diagnostic procedures in this age group. This study shows that mt-sDNA has high specificity among average-risk 45 to 49-year olds, supporting its use as a noninvasive option for colorectal cancer screening. Prevention Relevance: This study shows that mt-sDNA has high specificity among average-risk 45–49 year olds, supporting its use as a non-invasive option for colorectal cancer screening.